Project Summary Glycans have critical biological and medical importance, yet understanding of their structure and function lags behind that of proteins for conceptual reasons and technical reasons. This Supplement will focus on a key component and highly dynamic aspect of the vertebrate glycome that has remained intractable to routine analysis: the diverse array of terminal sialic acids (Sias), and their linkages to underlying glycans. Sialoglycans on cell surface and secreted molecules, including mucins, play crucial roles in many physiological and pathological processes. Exploring the functions of Sias in different areas of health and disease requires analytical tools that are specific and reliable, and can be utilized by a wide range of investigators beyond the pioneers in glycobiology. Originally supported by NIH award U01 CA199792 ?Sialoglycan-recognizing probes (SGRPs) for defining sialoglycomes in biological systems?, Dr. Ajit Varki at UC San Diego developed a powerful new set of probes for Sias with different modifications and linkages. These probes are now available to early adopters for utilization in different biological systems. Sias are highly abundant in the intestinal tract and are associated with important digestive diseases, but many of the details remain unknown. The Supplement will apply the new SGRPs and underlying technology to the exploration of the host-microbial interface and inflammatory responses in the intestinal tract. The parent award for this Supplement, P30 DK120515 (MPI: Eckmann/Schnabl), supports the San Diego Digestive Diseases Research Center (SDDRC), a consortium that aims to provide scientific core services in human translational studies, murine infection and inflammation models, and microbiomics and functional genomics to more than 40 members engaged in digestive diseases research. Several SDDRC members, including the key personnel of this proposal, Drs. Eckmann and Rivera-Nieves, focus on immunology and infectious diseases, thus bringing a wealth of organ-specific expertise to the project within the scope of the parent award but lacking skills in glycoscience. The team will closely collaborate with the glycoscience pioneer, Dr. Varki, who is located in the same research building at UC San Diego, to validate the utility of the new glycoscience tools and refine their practical use for multi-dimensional single-cell analysis in different digestive disease models. Furthermore, SDDRC provides an ideal platform to provide access to and adoption of new glycoscience technology and reagents, and to coordinate intense collaboration between non-specialists in need of new glycoscience tools and glycoscience pioneers to validate and apply new tools and methods in the investigation of digestive diseases. This collaboration has outstanding potential to advance both digestive diseases research and glycoscience.